(a) Field of the Invention
The present invention relates to a process for preparing 2-methyl-2′-phenylpropionic acid derivatives, novel intermediate compounds and their preparation processes used therefor.
(b) Description of the Related Art
2-methyl-2′-phenylpropionic acid derivatives of the following Formula 1 show excellent antihistamine activity and antiallergic activity, and thus widely used in the field of pharmaceutics.
                wherein, A is oxygen or nitrogen; R1 is hydrogen or C1-C6 linear or branched alkyl when A is oxygen, and R1 together with A forms a 5 to 7-membered ring unsubstituted or substituted with C1-C6 linear or branched alkyl when A is nitrogen; R2 is hydrogen or —CH2CH2OR2′, provided that R2 is —CH2CH2OR2′ when A is nitrogen; and R2′ is hydrogen, C1-C6 linear or branched alkyl, C3-C6 cyclic alkyl, or C2-C6 alkenyl.        
Particularly, 2-methyl-2′-phenylpropionic acid derivatives exclusively have H1 antihistamine activity. Thus, they show high selectivity without acting with other pharmaceutical receptors even at higher dose. Therefore, 2-methyl-2′-phenylpropionic acid derivatives can be useful for a patient having allergic diseases, particularly for a patient who simultaneously receives other medicines, for example, those having cardiovascular disease (U.S. Pat. No. 5,877,187).
Meanwhile, EP 0818454 discloses a process for preparing 2-methyl-2′-phenylpropinoic acid derivatives belong under the Formula 1. However, this process majorly has two disadvantages as follows.
First, preparation of an intermediate compound having oxaozle group introduced therein and hydrolysis of oxazole group are inevitably comprised in the process, making the whole process complicated. Second, in an another intermediate compound, N—H bonds capable of N-alkylation exist at imidazole group as well as piperidinyl group, and thus, plenty of by-products may be generated. Accordingly, the process is inefficient to obtain 2-methyl-2′-phenylpropionic acid derivatives of the Formula 1 on industrial scale.
Meanwhile, J. Med. Chemistry (1986, 29, 1178-1183) and J. Heterocyclic Chem. (1987, 24, 31-37) describes a process for preparing piperidinyl benzoimidazole derivatives. However, this process use highly inflammable zinc powder in the step of reducing nitro group to amine group, and the yield is very low as about 30%, thus inappropriate for industrial scale production.
For the above reasons, there still have been demands for improvement of yield or purity of pharmaceutically useful 2-methyl-2′-phenylpropionic acid derivatives and their preparation process suitable for industrial scale production.